PART I THE SELEHXUM DKHYDKOOKNATIOH OF URSOLIC ACIB PART II THE PREPARATION OF MBTBOXY AC 8 TAL&EBYCB BY BARRY II * DUVALL01 Cl n€ m LD o7 ? 3 , Ml od X V v a U , H - M r+i; &- Thesis submitted to the Faculty of the Graduate School of the University of Merylend In partial fulfillment of the requirements for the degree of Doctor of Philosophy* CHEMISTRY LIBRARY 1956 * jjniverslty o p m a r y l a h d UMI Number: DP70323 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. UMI Dissertation Publishing UMI DP70323 Published by ProQuest LLC (2015). Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 ACKNOWLEDGMENT The writer wished to express his appreciation to Dr* N* L. Drake for suggesting these problems and for his constant advice and attention during the course of this research. TABLE OF C0HTE8TS FART I The Selenium Dehydrogenation of Orsolie Acid Page 1* Historical Introduction 1 A. Ursolic Acid ....... ............ 1 B« Selenium Dehydrogenation .......... 25 2* Experimental Part ......... ...... 41 A* Purification of Ursolic Acid ........... 41 B. Dehydrogenation Experiments ...... 44 5* Discussion of Results ...................... SO 4 • Summary ......... 62 Bibliography 64 PART II The Preparation of Methoxy Acetaldehyde, CHgOCHgCEO 1. Introduction .... 67 2m Previous work ....... 67 3 « Methods and Apparatus Used ......... 69 4* Preparation of Catalysts 72 5* Materials Used ..... 76 6m Investigation of Catalysts 76 7. Characterization of Methoxy Acetaldehyde..•. 35 8 . Conclusion ......... 90 Bibliography ....... 92 PABT X 1* HISTOBICAL XiTKODUCfXOS A* Ursolic acid The earliest reference to ursolic acid recorded in the literature was ®ade by Tromaadorf* In IBM* He Isolated fro® the leaves of the bearberry (Aretostaphylos Uva Ursi) two crystalline compounds, one called arbutln and the other called by Troanasdorf urson. The first thorough examination of this latter compound was made by Gintl^* who worked on a preparation obtained from Merk* Ursolic acid is widely distributed throughout the plant klndgom; a list of the sources is given below®* 7*8 i Chlmaphila umbellate Ilex Aquifolium Pirola rotundifolia Ilex paraguarlensle Rhododendron maximum Ilex cremate Bpigaea repens Ilex perado Gaultherla procumbena Pirola umbellate Calluma vulgaris Vaccinlum Vitls Xdaea Erica Tetrallx Erica arborea Vaccinlum saerooarpus Pirola minor Vaccinlum Myrtlllus Erica mediterranea Azalea Indies Erica carnea Bhododendron hybridum VI scum Album Arbutus Andrachne Apples* pears and cranberries In all except the last three sources, the ursolic acid occurs in the leaves of the plants mentioned* In the latter sources* the ursolic acid la found in the wax-like coating on the surface of the apple* In the skin of the pear, and In cranberry pomace« There are several methods of Isolating ursolic acid from Its natural sources* Three of these methods will be given in some detail* Nooyen^ investigated the following methods of Isolations 1* the method of Trommsdorf (1)* 2* the method of Vanltallle (9) 3* the method of Dodge (10)* She obtained the most satisfactory results from the third 10 method which is described by Dodge in the following manners * 2 0 0 g* of commercial 0 va Drsi was thoroughly dried* pulverised* and mixed with one liter of methyl alcohol and 150 ec of 2 1 alcoholic potassium hydroxide* and allowed to stand several days with frequent shaking* The mixture was then filtered* and the residue washed clean with about 500 ec of methyl alcohol* The combined filtrate and washings were acidified with acetic acid and concentrated to about 300 ec* On cooling* greenish crystals* amounting to about 4 g* were deposited and on further concentrating a more impure product (7 g) was obtained* By recrystall! jsstlon from alcohol, with bone black* 5 g of white crystals were obtained*" Sando® used a method devised by him* which he describes thus: m $ m ^The ether-soluble extract of the dried pear skins (a 150 g. portion) was treated three times with boiling dilute aqueous sodium hydroxide, whereupon soluble and Insoluble sodium salts were formed* These were separated through a Buchner funnel* The crude, water-in- soluble sodium salt was dissolved in boiling 95^ ethyl alcohol containing a small amount of sodium hydroxide, and an equal quantity of hot water added* The solution was maintained at the boiling point and stirred mechanically until the sodium salt had separated. The hot solution was filtered and the salt washed and dried, after which it was extracted with ether for 7 days in a Soxhlet apparatus* The Insoluble salt was then recrystallised three times by the process described above. The free acid was recovered from its salt by solution of the latter in alcohol and addition of dilute hydrochloric acid# The nearly pure acid was filtered off, washed thoroughly with water, and dried* It weighed 58 g* Final purification was accomplished by several fractional crystallisations from absolute alcohol, whereby 25 g* of ursolic acid were obtained with a melting point of 282*5 - 283.S°*. Another method of isolating ursolic acid from its natural sources, suggested by the methods of Sand© and of Bodge, has been devised by Dr# H. L# Brake and the author* 4 The details of this method are given In the experimental part of this thesis* Belov are listed the physical properties of ursolic sold as have been observed by various investigators: Melting point**: 282.5-233.5°C. Optical Properties r 24*8^ 0 L0^ d m + 64*94 (ursolic acid) r°Q * ♦ 57*84° (potassium ursolate) Extinction ...... parallel Elongation •••.«»•*•*****»••••••••••.*•••••»•»•* positive Eetardation, in wave lengths .... ........ 1/4*^ Birefringence, from assumed thickness •*»••*•••• 0*0005 n 0 estimated •.»***.••»»•*•••*••••*•••*••**•»»•« 1*55-1*54 light Inconvergent shows • ....... .***..******•••••••acute bisectrix Optical angle* 2 ¥ .... 22-28° Crystals are probably *... •••*••**•**«••••• orthorhombic Habit is charac ter1s 11c * blades being present with sore cleavage crosswise* These show the Indices: c L , crosswise of blades * 1*56 - 0 * 0 1 (_3 f lengthwise « 1*56 - 0*01 T # perpendicular to the blades and measurable only on rare fragments which happen to turn on edge » 1*58 * 0*01 - 5 - Between crossed nlcols, Interference colors of the first and second order are distinguishable* In convergent polarised light, with crossed nicols, biaxial figures are shown with A . Q SB * 150° I 10 The optic sign is positive* The crystal system is inferred to be rhombic, with the direction of the index Q lying along the principal zone axis* Solubility of ursolic acid®* o 1 gt of ursolic acid at 16 C la 178 g ethyl alcohol 38 g methyl alcohol 388 g chloroform 192 g ethylene dlbromlde 140 g diethyl ether Color testa shown by ursolic acid®: 1. With conc. HgS0<|, ursolic acid gives an orange-yellow color with a green fluorescence* 2 * Llebermann tests a little ursolic acid dissolved in 2 ml* acetic anhydride gives with 8 to 1 0 drops of conc* B2 SO4 a red color which changes to violet to green to blue* For the different phases of these reactions the following absorption bands were noted t red s X ® ® 8*59® blu*iX6S2-664 green: X 618-670i - 6 - 3. A little ursolic acid dissolved In CBClg, when mixed with an equal volume of conc, HgSO^ gives directly s yellow color; with more conc. HgSO^ the color later changes to brown. The compound now known as ursolic acid was, prior is to 1924, known as urson. At this time van der Haar , as the result of a study of the compound, showed the former name to be more consistent with its chemical nature. There have been described In the earlier literature two compounds, raalol and pruaol, which van der Haar subse­ quently showed to be none other than ursolic acid. Malol was first reported by Sendo®. It was shown by van der Bear* 5 in 1924 to be ursolic acid. Frunol was first reported by Power and Moore** and in 1924 shown by van der Haar*** to be ursolic acid* The prunol of Power and Moore was Isolated from the leaves of frunus serotina* Orsolic acid is Isomeric with caryophyllin (Dodge,*®) is or oleanol 1 c add, the sugar-beet sapogenln (van der Haar )• Caryophyllin and oleanolic acid are the same substance. 1 frommsdorf assigned to ursolic a d d the formula <c10%e$)n, Hlsalweta*® and Kochleder* 7 also reported analyses of ursolic add, the former finding the composition (C1 0 H 1 7 0)n, the letter agreeing with Trcamadorf. Olntl® aleo reported for ureollc acid the formula - 7 - ( C ^ o % 6 °^n wliere & * S as determined by a molecular weight determination* Hooyen® obtained results in agreement with those of Qintl, i.e., (Cio%gO)n where n • The latter investigator found the molecular weight of ursolic acid by both the freezing point depression and the boiling point elevation methods* bodge also favors the formula <CxoHigO)gj he determined the molecular weight by direct titration of the acid (he considers the compound to be a lactose, not an acid)* Sendo1 8 assigns to ursolic acid the formula He bases his formula on the statistical mean values of ninety-two analyses of ursolic acid and its derivatives*